ISSN: 1449-2288International Journal of Biological Sciences
Global reach, higher impact
Int J Biol Sci 2024; 20(4):1160-1179. doi:10.7150/ijbs.90441 This issue Cite
Research Paper
Hepatobiliary organoids differentiated from hiPSCs relieve cholestasis-induced liver fibrosis in nonhuman primates
1. School of Life Science, Beijing University of Chinese Medicine, Beijing 100029, People's Republic of China.
2. Beizhong Jingyuan Biotechnology (Beijing) Limited, Beijing, People's Republic of China.
3. Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen 518116, People's Republic of China.
4. Tangyi Holdings (Shenzhen) Limited, Shenzhen, People's Republic of China.
5. State Key Laboratory of Biocontrol, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes, College of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, People's Republic of China.
# These authors contributed equally to this work.
Abstract
There is an urgent need for novel therapies to treat end-stage liver disease due to the shortage of available organs. Although cell transplantation holds considerable promise, its availability is limited due to the low engrafted cell mass and lack of unifying cell transplantation strategies. Here, we optimally established human induced pluripotent stem cell-derived functional hepatobiliary organoids (HBOs) based on our previous research and transplanted them into a monkey model via liver subcapsular and submesenteric transplantation routes to assess their potential clinical application. Our study revealed that HBO transplantation could safely and effectively improve hepatoprotection effects by antiapoptotic and antifibrotic agents. In addition, we also discovered that while multiple HBO transplantation pathways may have a shared effector mechanism, their respective treatment approaches have distinct advantages. Transplantation of HBOs could promote the high expression of CTSV in hepatic sinusoid endothelial cells, which might halt the progression of hepatic sinusoidal capillarization and liver fibrosis. Liver subcapsular transplants had stronger pro-CTSV upregulation than HBO submesenteric transplants, which could be attributed to naturally high CTSV expression in HBOs. Interestingly, both transplantation routes of HBOs were targeted the injured liver and triggered a new pattern of ductular reaction to alleviate the degree of liver fibrosis by surrounding the area with CK19-positive labeled cells. These residing, homing and repairing effects might be related to the high expression of MMP family genes. By promoting a unique pattern of ductular reactions, submesenteric HBO transplantation has a more representative antifibrotic impact than liver subcapsular transplantation. Altogether, our data strongly imply that the treatment of severe liver diseases with liver subcapsular and submesenteric transplantation of HBOs may be clinically effective and safe. These findings provide new insight into HBOs for further experimental and clinical validation.
Keywords: HBOs induced from hiPSCs, Liver subcapsular transplantation, Submesenteric transplantation, Safety and efficacy, Hepatoprotective effect and mechanism
Citation styles
